WO2002065977A2 - Composes co-induisant une regulation positive et une regulation negative de l'inflammation cholinergiques et des utilisations de ceux-ci - Google Patents

Composes co-induisant une regulation positive et une regulation negative de l'inflammation cholinergiques et des utilisations de ceux-ci Download PDF

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Publication number
WO2002065977A2
WO2002065977A2 PCT/IL2002/000122 IL0200122W WO02065977A2 WO 2002065977 A2 WO2002065977 A2 WO 2002065977A2 IL 0200122 W IL0200122 W IL 0200122W WO 02065977 A2 WO02065977 A2 WO 02065977A2
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Prior art keywords
residue
group
pharmaceutical composition
ibuprofen
inflammatory
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PCT/IL2002/000122
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English (en)
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WO2002065977A8 (fr
WO2002065977A3 (fr
Inventor
Gabriel Amitai
Rachel Adani
Ishai Rabinovitz
Gali Sod-Moriah
Haim Meshulam
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Israel Institute For Biological Research
Life Science Research Israel Ltd.
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Application filed by Israel Institute For Biological Research, Life Science Research Israel Ltd. filed Critical Israel Institute For Biological Research
Priority to EP02712224A priority Critical patent/EP1385824A2/fr
Priority to JP2002565538A priority patent/JP2004537504A/ja
Priority to CA002439898A priority patent/CA2439898A1/fr
Priority to IL15743602A priority patent/IL157436A0/xx
Publication of WO2002065977A2 publication Critical patent/WO2002065977A2/fr
Publication of WO2002065977A3 publication Critical patent/WO2002065977A3/fr
Publication of WO2002065977A8 publication Critical patent/WO2002065977A8/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4425—Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to preparation and use of novel
  • bifunctional chimeric compounds for the treatment of central nervous
  • invention relates to novel chimeric compounds which are conjugates of
  • NSAIDs anti-inflammatory drugs
  • AD Alzheimer's disease
  • cerebral spastic syndrome cerebral spastic syndrome
  • ChEI cholinesterase inhibitors
  • M2 cholinergic Ml agonists
  • beta amyloid peptide such as amyloid
  • APP precursor protein
  • ChEIs e.g., ARICEPT and EXELON.
  • ChE cholinesterase
  • ChEI ChEI with either muscarinic receptor agonist (Ml or M3) or M2
  • BChE and AChE are part of the complex comprising the
  • peripheral anionic-site inhibitors decreases the formation of these peripheral anionic-site inhibitors
  • BBB blood-brain barrier
  • NSAIDs anti-inflammatory drugs
  • the inducible form, COX-2 is formed by
  • AD treatment is limited by its possible side effects and toxicity. Moreover,
  • selective COX-2 inhibitors and are further able to cross the BBB, in order to
  • NSAIDs hardly cross the BBB, and the use thereof induces side effects
  • anti-inflammatory drugs can be useful for the treatment of acute cerebral spastic pain
  • hypoxic-ischemic damage is a glucocorticoid receptor-mediated effect (19).
  • NSAIDs have been shown to act as inhibitors
  • ENA-713 (EXELON) for either protection or treatment of neuronal damage
  • EXELON could be useful for treatment of senile dementia such as
  • cerebrovascular dementia and for reducing the neuronal damage caused by
  • new cholinergic compounds such as reversible or irreversible ChEIs, as well as new NSAIDs, can be useful for the treatment and prevention of
  • cholinergic up-regulators e.g., cholinergic up-regulators
  • ChEIs ChEIs
  • NSAIDs are each independently and via different
  • carboxylic acid group are hydrophihc by nature, as they interact with
  • NSAIDs non-steroidal anti-inflammatory drugs
  • hydrolytic derivatives due to the cholinergic up-regulator moiety the
  • chimeric compound comprising a cholinergic up-regulator moiety and a
  • non-steroidal anti-inflammatory moiety being covalently linked thereto.
  • A is a cholinergic up-regulator moiety selected from the group consisting of
  • a cholinesterase inhibitor residue a nicotinic receptor agonist residue and a
  • B is a non-steroidal anti-inflammatory
  • X is a non-substituted or substituted oxygen, sulfur or nitrogen atom
  • Y is a substituted or non-substituted carbon, oxygen, nitrogen, sulfur,
  • composition comprising, as an active ingredient
  • the pharmaceutical composition is formulated for transdermal delivery, nasal administration, administration by inhalation
  • the method comprising the step
  • the central nervous system disorder or disease is a substance that causes central nervous system disorder or disease.
  • Alzheimer's disease cerebrovascular
  • the organism is a mammal.
  • the mammal is a human being.
  • the method comprising the steps of (a) converting a non-steroidal
  • the method comprising the steps of (a) converting a non-steroidal
  • the method comprising the steps of (a) converting a cholinergic
  • non-steroidal anti-inflammatory drug so as to obtain the chimeric
  • the method further comprises
  • non-steroidal anti-inflammatory moiety are covalently linked via a
  • cycloalkyl having 3-20 carbon atoms and an aryl having 6-20 carbon atoms.
  • a cholinesterase inhibitor residue consisting of a cholinesterase inhibitor residue, a nicotinic receptor agonist
  • the pyridostigmine residue is a 3-N,N-dimethylcarbamoyl
  • naproxen residue a diclofenac residue and an aspirin residue.
  • a drug may be defined as a drug and/or a prodrug.
  • a reversible cholinesterase inhibitor having a general formula A:
  • R 2 is selected from the group consisting of hydrogen, an
  • alkyl a hydroxyalkyl, a haloalkyl, an alkylamine, a cycloalkyl and an aryl;
  • X is a halide
  • Q and Z are each independently selected from the group
  • R 3 is selected from the group
  • Q and Z are each oxygen, R 3 is methyl, R 2 is an
  • alkyl and X is selected from the group consisting of bromide and iodide.
  • R 2 is selected from the group consisting of hydrogen, an
  • alkyl a hydroxyalkyl, a haloalkyl, an alkylamine, a cycloalkyl and an aryl;
  • Q and Z are each independently selected from the group consisting of
  • R 3 is selected from the group consisting of an alkyl
  • Q and Z are each oxygen, R 3 is methyl and R 2 is
  • the reactive inorganic halide is potassium iodide.
  • organic halide is the R 2 residue terminating with the
  • the present invention successfully addresses the shortcomings of the
  • FIGs. la-b are plots demonstrating a time-course of HuAChE
  • FIG. 2 is a plot demonstrating a time-course of whole blood ChE
  • FIG. 3 shows photographs of rat stomach mucosal tissue following
  • FIG. 4 is a bar graph demonstrating a decrease in
  • FIG. 5 is a comparative bar graph demonstrating an effect of IBU
  • FIG. 6 is a bar graph demonstrating the effect of intraperitoneal
  • FIG. 7 shows comparative plots demonstrating the effect of
  • IBU-PO-induced by intraperitoneal injection of 2.5 mg/kg IBU-PO
  • FIG. 8 is a bar graph demonstrating the effect of varying doses of
  • FIG. 9 is a bar graph demonstrating the effect of treatment with
  • FIG. 10 is a bar graph demonstrating the effect of IBU-PO and
  • FIG. 11 shows plots demonstrating the competition binding curves
  • FIG. 12 shows plots demonstrating the competition binding curves
  • the present invention is of chimeric compounds which are
  • NSAIDs non-steroidal anti-inflammatory drugs
  • novel reversible NSAIDs non-steroidal anti-inflammatory drugs
  • CNS nervous system disorders and diseases, such as, but not limited to,
  • Alzheimer's disease cerebrovascular dementia, cerebral ischemia, transient
  • hypoxia and stroke as well as CNS diseases or disorders induced by closed
  • chimeric compound covalently coupling a cholinergic up-regulator moiety
  • non-steroidal anti-inflammatory drugs especially those comprising a
  • invention includes a cholinergic up-regulator moiety and a non-steroidal
  • anti-inflammatory moiety which are covalently coupled.
  • cholinergic up-regulator moiety refers to a residue
  • Acetylcholine (ACh) is a neurotransmitter that is constantly
  • ChAT decomposed by cholinesterase (ChE) and exerts its cholinergic
  • cholinergic up regulation can be
  • ChEs by inhibition of ChEs; and/or (iii) mimicking its action via agonists directed
  • cholinergic compounds according to the present invention
  • ChEI cholinesterase inhibitors
  • a pyridostigmine a pyridostigmine
  • nicotinic receptor agonists such as, but not
  • nicotine and cytisine or muscarinic receptor agonists such as,
  • NSAID non-steroidal anti-inflammatory
  • NSAIDs according to the present invention include, for example,
  • ibuprofen indomethacin, naproxen, diclofenac and aspirin.
  • non-steroidal anti-inflammatory moiety is an (+)-ibuprofen residue, an
  • isomer S-(+)-ibuprofen also referred to in the art as dexibuprofen, is known
  • R-(-)-ibuprofen which is known to act as an effective anti-inflammatory
  • the cholinergic up-regulator moiety and the NSAID moiety are covalently
  • hydrocarbon refers to a compound that includes
  • hydrocarbon can be saturated, unsaturated, branched or unbranched.
  • hydrocarbon spacer refers to a hydrocarbon moiety
  • hydrocarbon such as, but not limited to, alkyl
  • alkyl refers to a saturated aliphatic hydrocarbon
  • alkyl including straight chain and branched chain groups.
  • the alkyl Preferably, the alkyl
  • cycloalkyl refers to an all-carbon monocyclic or fused
  • ring groups i.e., rings which share an adjacent pair of carbon atoms
  • aryl refers to an all-carbon monocyclic or fused-ring
  • polycyclic group i.e., rings which share adjacent pairs of carbon atoms
  • aryl groups are phenyl, naphthalenyl and anthracenyl.
  • NSAID moiety is covalently attached to the hydrocarbon spacer via a
  • Y is, without limitation, a
  • Y is, without limitation, oxygen
  • R' is hydrogen, alkyl, cycloalkyl or aryl.
  • R' is as defined above.
  • R' is as defined above.
  • R' is as defined above.
  • X is, without limitation, oxygen or sulfur
  • Y is, without limitation
  • amine refers to a -NR'- group, where R' is hydrogen
  • alkyl cycloalkyl or aryl.
  • R' is as defined above.
  • R' is as defined above.
  • ester bond is a carboxylic ester bond or a glycol amide ester bond.
  • glycol amide ester bond refers to a
  • the chimeric compound is characterized by cholinergic
  • invention refers to the products formed in vivo by the enzymatic hydrolysis
  • present invention is exerted by both a prodrug, which is the parent chimeric
  • chimeric compound is a NSAID-PYR-X compound whose chemical
  • R is one of:
  • NSAID-PYR-X refers to a chimeric compound
  • the chimeric compound is an IBU-4H-PO compound whose chemical
  • IBU-4H-PO refers to 2-(4-isobutyl phenyl)-propionic
  • the chimeric compound is an IBU-OCT-cytisine compound (nicotinic receptor agonist) whose chemical structure is described in
  • IBU-OCT-cytisine refers to ibuprofen
  • the compounds IBU-OCT-arecoline (a muscarinic receptor
  • IOA insulin receptor agonist
  • IOMN IBU-OCT-methylnicotinate
  • IBU-OCT-arecoline IBU-OCT-methylnicotinate (IOMN)
  • IBU-OCT-arecoline refers to IBU-OCT-arecoline
  • IBU-OCT-methyl nicotinate refers to l- ⁇ 8-[2-
  • the active site of the enzyme the active site of the enzyme, the IOMN and IOA compounds interact with
  • a reversible cholinesterase inhibitor having a general formula A:
  • R 2 is selected from the group consisting of hydrogen, an
  • alkyl a hydroxyalkyl, a haloalkyl, an alkylamine, a cycloalkyl and an aryl;
  • X is a halide
  • Q and Z are each independently selected from the group
  • R 3 is selected from the group
  • R 2 is selected from the group consisting of hydrogen, an
  • alkyl a hydroxyalkyl, a haloalkyl, an alkylamine, a cycloalkyl and an aryl;
  • Q and Z are each independently selected from the group consisting of oxygen and sulfur; and R 3 is selected from the group consisting of an alkyl,
  • haloalkyl as used herein in the specification and in the
  • hydroxyalkyl refers to an alkyl group as
  • alkylamine refers to an alkyl group as
  • anti-inflammatory-ester which includes a hydrocarbon chain terminating
  • chimeric compound having a cholinergic up-regulator moiety and a
  • non-steroidal anti-inflammatory moiety being covalently linked thereto via
  • the reactive halide group can be fluoride, chloride, bromide, or
  • esterified anti-inflammatory drug is reacted with a cholinergic
  • up-regulator which includes a pyridine ring to form a chimeric compound
  • anti-inflammatory moiety being covalently linked thereto via a hydrocarbon
  • anti-inflammatory-amide which includes a hydrocarbon chain terminating
  • a chimeric compound having a cholinergic up-regulator moiety and a non-steroidal anti-inflammatory moiety being covalently linked thereto via
  • amide derivative is reacted with a cholinergic up-regulator which includes a
  • up-regulator moiety and a non-steroidal anti-inflammatory moiety being
  • the derivative includes a hydrocarbon chain terminating with a
  • this method further includes the step of converting the
  • a cholinergic up-regulator which includes a ring
  • hydrocarbon terminated with a hydroxyl is reduced into a tertiary amine
  • anti-inflammatory drug is then esterified by the hydroxyl of the tertiary
  • up-regulator moiety and a non-steroidal anti-inflammatory moiety being
  • R' is, without limitation, alkyl, cycloalkyl or aryl, as defined
  • alkyl are alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkylamine and aryl, as
  • halide group is bromide and iodide.
  • a reactive inorganic halide is potassium
  • organic halide refers to a substituted or
  • non-substituted residue as defined hereinabove, that includes a halide group
  • a pyridine ring that is substituted at position 3 by a
  • carboxylate group such as methyl nicotinate
  • non-substituted alkyl terminating with a halide group such as bromide or
  • composition including the chimeric compound of the
  • composition refers to a pharmaceutical composition
  • composition The purpose of a pharmaceutical composition is to
  • excipient refers to an inert substance
  • excipients include
  • Suitable routes of administration may,
  • parenteral delivery including intramuscular, subcutaneous and
  • intravenous, intraperitoneal, intranasal, or intraocular injections are intravenous, intraperitoneal, intranasal, or intraocular injections.
  • composition/formulation Pharmaceutical compositions of the
  • present invention may be manufactured by processes well known in the
  • compositions for use in accordance with the present invention are provided.
  • compositions comprising excipients and
  • auxiliaries which facilitate processing of the active compounds into
  • the compounds of the invention may be formulated in
  • aqueous solutions preferably in physiologically compatible buffers such as
  • penetrants are used in the formulation.
  • Such penetrants are generally known in the art.
  • the compounds can be formulated readily
  • inventions to be formulated as tablets, pills, dragees, capsules, liquids, gels,
  • Pharmacological preparations for oral use can be made using a solid
  • Suitable excipients are, in particular, fillers such
  • sugars including lactose, sucrose, mannitol, or sorbitol; cellulose
  • preparations such as, for example, maize starch, wheat starch, rice starch,
  • physiologically acceptable polymers such as polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as cross-linked
  • polyvinyl pyrrolidone agar, or alginic acid or a salt thereof such as
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose,
  • concentrated sugar solutions may be used which may optionally contain
  • gum arabic talc
  • polyvinyl pyrrolidone carbopol gel
  • polyethylene glycol polyethylene glycol
  • compositions which can be used orally, include
  • gelatin gelatin and a plasticizer, such as glycerol or sorbitol.
  • a plasticizer such as glycerol or sorbitol.
  • capsules may contain the active ingredients in admixture with filler such as
  • lactose binders such as starches, lubricants such as talc or magnesium
  • the active in soft capsules, the active
  • fatty oils liquid paraffin, or liquid polyethylene glycols.
  • liquid paraffin or liquid polyethylene glycols.
  • compositions may take the form of
  • a suitable propellant e.g., dichlorodifluoromethane
  • the dosage unit may be determined by
  • gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base
  • chimeric compounds described herein may be formulated for
  • parenteral administration e.g., by bolus injection or continuos infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in
  • compositions may be suspensions, solutions or
  • emulsions in oily or aqueous vehicles may contain formulatory agents
  • suspending, stabilizing and/or dispersing agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include
  • suspensions of the active compounds may be prepared as
  • fatty oils such as sesame oil, or synthetic fatty acids esters
  • suspensions may contain substances, which increase the viscosity of the
  • suspension such as sodium carboxymethyl cellulose, sorbitol or dextran.
  • the suspension may also contain suitable stabilizers or agents
  • the active ingredient may be in powder form for
  • a suitable vehicle e.g., sterile, pyrogen-free water
  • chimeric compounds of the present invention may also be any organic compound that is suitable for use.
  • the chimeric compounds of the present invention may also be any organic compound that is suitable for use.
  • the chimeric compounds of the present invention may also be any organic compound that is suitable for use.
  • compositions such as suppositories or retention
  • enemas using, e.g., conventional suppository bases such as cocoa butter or
  • compositions herein described may also be referred to be pharmaceutical compositions herein described.
  • Such carriers or excipients include, but are not limited to, calcium
  • gelatin derivatives, gelatin and polymers such as polyethylene glycols.
  • a therapeutically effective amount means an
  • a dose can be formulated in
  • the IC 50 as determined by activity assays e.g., the concentration of the test compound, which achieves a half-maximal inhibition of the ChE or COX
  • Such information can be used to more accurately determine
  • experimental animals e.g., by determining the IC 50 and the LD 50 (lethal
  • the dosage may vary depending upon the dosage form employed
  • administration and dosage can be chosen by the individual physician in
  • Dosage amount and interval may be adjusted individually to
  • ChE cholinesterase
  • MEC concentration
  • bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using the MEC value.
  • Preparations should be administered using a regimen, which maintains
  • dosing can also be a single administration of a slow release
  • compositions to be administered will, of course, be
  • compositions of the present invention may, if desired,
  • a pack or dispenser device such as an FDA approved kit
  • the pack may, for example, comprise metal or plastic foil,
  • the pack or dispenser device may be accompanied
  • the pack or dispenser may also be
  • Such notice for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an
  • compositions comprising a chimeric compound
  • label may include treatment of an Alzheimer's disease, cerebral ischemia,
  • the method is a method for treating a disorder or disease in an organism (e.g., a human being).
  • the method is
  • treating includes abrogating, substantially
  • CNS disorder or disease refers to a
  • administering refers to a method for
  • organism refers to animals, typically mammals having a
  • blood brain barrier including human.
  • terapéuticaally effective amount refers to that amount
  • the present invention is thus directed to chimeric compounds
  • treatable using the chimeric compounds of the invention include, without
  • Alzheimer's disease cerebrovascular dementia
  • Parkinson's Parkinson's
  • treatable using the chimeric compounds of the invention include, without limitation, cerebral ischemia, transient hypoxia, and stroke. Further
  • disorders can be induced by closed head injury, infection, tumor and
  • the method is a method for treating a disorder or disease in an organism (e.g., a human being).
  • the method is
  • the reversible cholinesterase inhibitors of the invention cause
  • Oxalyl chloride 11 grams, 86 mmol was then added dropwise, and

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Abstract

L'invention concerne des composants chimériques qui sont des conjugués covalents de médicaments anti-inflammatoires non-stéroïdiens et régulateurs positifs cholinergiques réversibles ou irréversibles (NSAID), des procédés pour leur synthèse et l'utilisation de ceux-ci dans le traitement et/ou la prévention des troubles et maladies du système nerveux central (CNS).
PCT/IL2002/000122 2001-02-20 2002-02-17 Composes co-induisant une regulation positive et une regulation negative de l'inflammation cholinergiques et des utilisations de ceux-ci WO2002065977A2 (fr)

Priority Applications (4)

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EP02712224A EP1385824A2 (fr) 2001-02-20 2002-02-17 Composes co-induisant une regulation positive et une regulation negative de l'inflammation cholinergiques et des utilisations de ceux-ci
JP2002565538A JP2004537504A (ja) 2001-02-20 2002-02-17 コリン作用アップレギュレーション及び炎症ダウンレギュレーションを共誘導する化合物、並びにその使用
CA002439898A CA2439898A1 (fr) 2001-02-20 2002-02-17 Composes co-induisant une regulation positive et une regulation negative de l'inflammation cholinergiques et des utilisations de ceux-ci
IL15743602A IL157436A0 (en) 2001-02-20 2002-02-17 Compounds co-inducing cholinergic up-regulation and inflammation down-regulation and uses thereof

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WO2004092728A2 (fr) * 2003-04-07 2004-10-28 Praecis Pharmaceuticals, Inc. Procede pour mesurer la capacite d'un compose test a inactiver une cible biologique dans les cellules d'un sujet
WO2005002519A3 (fr) * 2003-06-27 2005-09-01 Jackson H M Found Military Med Composes de pyridinium amphiphiles, leurs procedes de fabrication et d'utilisation
EP1610776A2 (fr) * 2003-03-27 2006-01-04 Merck & Co. Inc. Compositions ophtalmiques pour traiter une hypertension oculaire
WO2008110351A2 (fr) * 2007-03-15 2008-09-18 Dompe' Pha.R.Ma S.P.A. Utilisation de dérivés d'acides -2-aryl-propioniques (r) et (s) en tant qu'agents antiseptiques;
WO2009037705A2 (fr) * 2007-09-20 2009-03-26 Ramot At Tel Aviv University Ltd. Méthodes et compositions utiles pour le traitement du cancer et de l'inflammation
US8278357B2 (en) 2002-10-21 2012-10-02 Ramot At Tel-Aviv University Ltd. Derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel and/or neuron activity modulators
JP2013035863A (ja) * 2003-07-29 2013-02-21 Signature R&D Holdings Llc アミノ酸プロドラッグ
US8765815B2 (en) 2007-09-20 2014-07-01 Ramot At Tel-Aviv University Ltd. N-phenyl anthranilic acid derivatives and uses thereof

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ITMI20012025A1 (it) * 2001-09-28 2003-03-28 Dompe Spa Sali di ammonio quaternari di omega-amminoalchilammidi di acidi r 2-aril-propionici e composizioni farmaceutiche che li contengono
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US8039459B2 (en) 2004-07-15 2011-10-18 Universite Laval Nicotinic receptor agonists for the treatment of inflammatory diseases
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CA2913149A1 (fr) 2013-05-21 2014-11-27 Predictive Therapeutics, LLC Therapeutique et procede d'utilisation
CN105461731B (zh) * 2014-08-07 2017-05-24 富力 连翘脂素布洛芬酯、其制备及其应用
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US8278357B2 (en) 2002-10-21 2012-10-02 Ramot At Tel-Aviv University Ltd. Derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel and/or neuron activity modulators
US8618169B2 (en) 2002-10-21 2013-12-31 Ramot At Tel-Aviv University Ltd. Derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel and/or neuron activity modulators
EP1610776A4 (fr) * 2003-03-27 2007-03-28 Merck & Co Inc Compositions ophtalmiques pour traiter une hypertension oculaire
US7414067B2 (en) 2003-03-27 2008-08-19 Merck & Co. Inc. Ophthalmic compositions for treating ocular hypertension
EP1610776A2 (fr) * 2003-03-27 2006-01-04 Merck & Co. Inc. Compositions ophtalmiques pour traiter une hypertension oculaire
WO2004092728A2 (fr) * 2003-04-07 2004-10-28 Praecis Pharmaceuticals, Inc. Procede pour mesurer la capacite d'un compose test a inactiver une cible biologique dans les cellules d'un sujet
WO2004092728A3 (fr) * 2003-04-07 2005-06-02 Praecis Pharm Inc Procede pour mesurer la capacite d'un compose test a inactiver une cible biologique dans les cellules d'un sujet
US7893094B2 (en) 2003-06-27 2011-02-22 The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. Amphiphilic pyridinium compounds, method of making and use thereof
WO2005002519A3 (fr) * 2003-06-27 2005-09-01 Jackson H M Found Military Med Composes de pyridinium amphiphiles, leurs procedes de fabrication et d'utilisation
AU2004253541B2 (en) * 2003-06-27 2010-10-28 Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. Amphiphilic pyridinium compounds, method of making and use thereof
JP2013035863A (ja) * 2003-07-29 2013-02-21 Signature R&D Holdings Llc アミノ酸プロドラッグ
WO2008110351A2 (fr) * 2007-03-15 2008-09-18 Dompe' Pha.R.Ma S.P.A. Utilisation de dérivés d'acides -2-aryl-propioniques (r) et (s) en tant qu'agents antiseptiques;
WO2008110351A3 (fr) * 2007-03-15 2009-04-30 Dompe Pha R Ma Spa Res & Mfg Utilisation de dérivés d'acides -2-aryl-propioniques (r) et (s) en tant qu'agents antiseptiques;
WO2009037705A3 (fr) * 2007-09-20 2009-07-09 Univ Ramot Méthodes et compositions utiles pour le traitement du cancer et de l'inflammation
WO2009037705A2 (fr) * 2007-09-20 2009-03-26 Ramot At Tel Aviv University Ltd. Méthodes et compositions utiles pour le traitement du cancer et de l'inflammation
US8765815B2 (en) 2007-09-20 2014-07-01 Ramot At Tel-Aviv University Ltd. N-phenyl anthranilic acid derivatives and uses thereof
US9403756B2 (en) 2007-09-20 2016-08-02 Ramot At Tel-Aviv University Ltd. N-phenyl anthranilic acid derivatives and uses thereof

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EP1385824A2 (fr) 2004-02-04
CA2439898A1 (fr) 2002-08-29
WO2002065977A8 (fr) 2004-05-27
WO2002065977A3 (fr) 2003-12-04
IL157436A0 (en) 2004-03-28
US20020160988A1 (en) 2002-10-31

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